Chicago-based filmmaker Ben Byer and Clive Svendsen, UW-Madison professor of anatomy and physiology, met four years ago while Byer was filming neurology experts for his documentary, Indestructible."" At the time, Svendsen was one of many researchers being interviewed about the nature, cause and possible treatments for amyotrophic lateral sclerosis (ALS) - a devastating neurological disease that paralyzes and ultimately kills within two to five years. During that meeting, Ben was already visibly suffering the effects of ALS, also known as Lou Gehrig's disease, after the famous American baseball player who first brought the disease to the public's attention. Though Svendsen's footage never made the final cut of the film, his friendship with Byer has since continued.
""Ben was about my age when he was diagnosed, and it struck me very hard,"" said Svendsen. ""So I wanted to help in any way I could.""
Last Thursday, in front of a packed auditorium at UW-Madison's Waisman Center, Byer screened ""Indestructible,"" a powerful documentary about his ALS diagnosis and his quest to better understand the disease.
ALS is a neurological disorder that leads to the death of motor neurons throughout the entire body and is characterized by progressive muscle atrophy and weakness. According to the ALS Association, Byer is one of approximately 30,000 people currently living in the United States with the disease.
ALS is particularly devastating because unlike many other neurological disorders, the disease progresses quickly and there are no drugs available to treat the symptoms or slow the progression of the disease. The limitations of science to slow or stop ALS has frustrated researchers, and has, as the film poignantly notes, ""brought them to their knees.""
When diagnosed, Byer knew what the end game would likely be: full-body paralysis and the inability to communicate his thoughts and feelings. Instead of letting the disease silence him, Byer chose to document his journey with ALS using the tools he knew how to wield best: his own charismatic personality and the unsentimental, all-seeing eye of a movie camera.
""Indestructible"" follows Byer's three-year global quest for cures, as he tries everything from the Chinese herbal concoction Bu Nao Gao, to radical and controversial spinal cord surgery. On his blog, he confesses to having tried over thirty therapies in five years. These unsuccessful forays show the lengths to which ALS sufferers will go to try to halt or rid themselves of the disease.
Now confined to a wheelchair, Byer takes insulin-like growth factor-1 (IGF-1), a hormone that has not been approved by the FDA to treat ALS because of legal wrangling between competing pharmaceutical companies. Svendsen, who is familiar with the therapy and the legal issues surrounding it, counts this among the many sad obstacles faced by ALS patients.
When asked how he felt about the current state of ALS research, Byer said, ""I have great hopes for Dr. Svendsen's work.""
*The course of ALS*
Motor neurons make it possible for us to move any muscle. If you want to raise your right leg, the receiving end of a motor neuron, or dendrite, will be alerted with a message saying, ""raise right leg."" The signal is then sent down a long neuronal cable to the synapse of a waiting motor neuron in the spinal cord. According to Svendsen, the axons running from brain motor neurons to the spinal cord neurons are the ""longest connections in the universe."" Once a motor neuron in the spine receives the message, it then transmits signals out to muscle cells in the legs. The muscle receives the message, contracts, and through a series of relays, the right leg raises.
""With ALS, the problem is not that information ceases to be conveyed to the brain motor neuron,"" Svendsen said. ""The problem is that the neuron itself dies. So the connections are all just hanging around, but they have nothing to connect to. With the dead neuron, the cable has nothing to connect to, so the axon starts to degenerate.""
""The motor neuron die-off can start anywhere in the body, upper or lower, and then spread. You can start with a weak left arm and the right arm will be fine, then six months later, the right arm gets weak,"" Svendsen said. ""You can feel the disease crawling its way across your body. When the last motor neuron dies, you can't flick a muscle - o whether it's your eye muscle or your arm muscle.""
*Risk factors for ALS*
Although there are very few known risk factors, patterns have emerged. Caucasians are more likely to get the disease, and overall, males are at higher risk than females at a ratio of about 1.5 to 1. The disease is also seen more in northern climates and seems to strike high-achieving athletes in greater proportion, suggesting a possible link with physical trauma.
Researchers have also identified a genetic marker for the disease - a mutation in a gene called SOD-1. As noted on the ALS Association website, the SOD-1 mutation ""is believed to make a defective protein that is toxic to motor nerve cells."" Only 10 percent of all ALS cases can be attributed to a genetic mutation, and of those 10 percent, only 20 percent can be traced to the SOD-1 gene. The remaining 90 percent of ALS cases are sporadic. Despite its low prevalence, scientists have studied the SOD-1 mutation extensively in the lab by using mice programmed with the mutation that can reliably demonstrate the course of the disease, giving researchers the opportunity to try to combat the disease with various drugs.
*Scientists attempt to stop the disease in its tracks*
Svendsen's lab is using the SOD-1 model and taking a two-pronged approach to bringing deadened motor neurons back to life. The first part of the strategy involves detoxifying the neuronal environment.
""Motor neurons are these huge, prestigious, crystal structures, but they are useless on their own. It's kind of like a chandelier not being plugged in to the wall,"" Svendsen said.
Motor neurons are surrounded by support cells called astrocytes, large star-shaped ""nurse cells"" in the brain that provide a webby anchoring for the motor neurons within the environment. They also regulate blood flow into and out of the brain and modulate neurotransmission. There is an emerging suspicion among researchers that the astrocytes get sick first, setting off a cascade of decay throughout the environment.
Svendsen's team has developed a method of reprogramming stem cells to behave like new astrocytes. This reprogramming also convinces the astrocytes to pump out glial derived neurotrophic factor (GDNF), a protein Dr. Svendsen describes as ""fertilizer for motor neurons."" GDNF is seen in high quantities during early human development to help in the process of axon outgrowth. It is neuroprotective and helps maintain connections to the muscle. However, the supply decreases with age. By reinfusing the neuronal environment with GDNF, Svendsen hopes to protect the degenerating motor neurons.
The second part of the strategy involves introducing GDNF to muscle cells as well. In the mouse model, his team discovered that even though the astrocytes in the brain were pumping out GDNF, the axon at the muscle end was not quite getting the message that it was healthy again. It suggested that a motor neuron lives in two different worlds: one environment in the brain and the other at the very end of the axon, which is a world of muscle.
By also infusing GDNF into muscle, they discovered that the lower motor neurons became responsive. So the two-pronged approach involves treating the two lives of the motor neuron: feeding the brain and feeding the muscle.
Svendsen's team is steadily working to get approval to begin recruitment for their clinical trial exploring the effectiveness of this therapy. The trial protocol will be complex due to the many moving parts: working with stem cells, teaming up with neurosurgeons to perform complex spinal operations and navigating the regulatory landscape to ensure the trial is run safely and efficiently.
For Byer, this work cannot begin soon enough, and Svendsen is keenly aware of that.
""We look at our patients, and it just makes us work that much harder.""
